{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T21:17:23Z","timestamp":1793222243022,"version":"4.5.0"},"reference-count":79,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T00:00:00Z","timestamp":1564099200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T00:00:00Z","timestamp":1564099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Soffer Family Foundation grant.","id":[{"id":"https:\/\/ror.org\/02xagqm21","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The infrapatellar fat pad (IFP) serves as a reservoir of Mesenchymal Stem Cells (MSC), and with adjacent synovium plays key roles in joint disease including the production of Substance P (SP) affecting local inflammatory responses and transmitting nociceptive signals. Here, we interrogate human IFP-derived MSC (IFP-MSC) reaction to inflammatory and pro-fibrotic environments (cell priming by TNF\u03b1\/IFN\u03b3 and TNF\u03b1\/IFN\u03b3\/CTGF exposure respectively), compared with bone marrow-derived MSC (BM-MSC). Na\u00efve IFP-MSC exhibit increased clonogenicity and chondrogenic potential compared with BM-MSC. Primed cells experienced dramatic phenotypic changes, including a sharp increase in CD10, upregulation of key immunomodulatory transcripts, and secreted growth factors\/cytokines affecting key pathways (IL-10, TNF-\u03b1, MAPK, Ras and PI3K-Akt). Na\u00efve, and more so primed MSC (both)\u00a0induced SP degradation\n                    <jats:italic>in vitro<\/jats:italic>\n                    , reproduced with their supernatants and abrogated with thiorphan, a CD10 inhibitor. These findings were reproduced\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a rat model of acute synovitis, where transiently engrafted human IFP-MSC induced local SP reduction. Functionally, primed IFP-MSC demonstrated sustained antagonism of activated human peripheral blood mononuclear cells (PBMC) proliferation, significantly outperforming a declining dose-dependent effect with na\u00efve cohorts. Collectively, our\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    data supports cell priming as a way to enhance the immunoregulatory properties of IFP-MSC, which selectively engraft in areas of active synovitis\/IFP fibrosis inducing SP degradation, resulting in a cell-based product alternative to BM-MSC to potentially treat degenerative\/inflammatory joint diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-47391-2","type":"journal-article","created":{"date-parts":[[2019,7,26]],"date-time":"2019-07-26T06:03:04Z","timestamp":1564120984000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation"],"prefix":"10.1038","volume":"9","author":[{"given":"Dimitrios","family":"Kouroupis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie C.","family":"Bowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa A.","family":"Willman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlotta","family":"Perucca Orfei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Colombini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee D.","family":"Kaplan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Correa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,7,26]]},"reference":[{"key":"47391_CR1","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1111\/joa.12820","volume":"233","author":"V Macchi","year":"2018","unstructured":"Macchi, V. et al. The infrapatellar fat pad and the synovial membrane: an anatomo-functional unit. J Anat 233, 146\u2013154 (2018).","journal-title":"J Anat"},{"key":"47391_CR2","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1016\/j.joca.2010.03.014","volume":"18","author":"S Clockaerts","year":"2010","unstructured":"Clockaerts, S. et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthr Cartil 18, 876\u2013882 (2010).","journal-title":"Osteoarthr Cartil"},{"key":"47391_CR3","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nrrheum.2017.53","volume":"13","author":"A Ioan-Facsinay","year":"2017","unstructured":"Ioan-Facsinay, A. & Kloppenburg, M. Osteoarthritis: Inflammation and fibrosis in adipose tissue of osteoarthritic joints. Nat Rev Rheumatol 13, 325\u2013326 (2017).","journal-title":"Nat Rev Rheumatol"},{"key":"47391_CR4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1007\/s11926-017-0672-6","volume":"19","author":"E Kalaitzoglou","year":"2017","unstructured":"Kalaitzoglou, E., Griffin, T. M. & Humphrey, M. B. Innate Immune Responses and Osteoarthritis. Curr Rheumatol Rep 19, 45 (2017).","journal-title":"Curr Rheumatol Rep"},{"key":"47391_CR5","first-page":"53","volume":"35","author":"J-B Gross","year":"2017","unstructured":"Gross, J.-B. et al. The infrapatellar fat pad induces inflammatory and degradative effects in articular cells but not through leptin or adiponectin. Clin. Exp. Rheumatol. 35, 53\u201360 (2017).","journal-title":"Clin. Exp. Rheumatol."},{"key":"47391_CR6","first-page":"17","volume":"24","author":"J-B Gross","year":"2014","unstructured":"Gross, J.-B., Guillaume, C., Gegout-Pottie, P., Mainard, D. & Presle, N. Synovial fluid levels of adipokines in osteoarthritis: Association with local factors of inflammation and cartilage maintenance. Biomed Mater Eng 24, 17\u201325 (2014).","journal-title":"Biomed Mater Eng"},{"key":"47391_CR7","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1093\/rheumatology\/kev228","volume":"54","author":"DFG Remst","year":"2015","unstructured":"Remst, D. F. G., Blaney Davidson, E. N. & van der Kraan, P. M. Unravelling osteoarthritis-related synovial fibrosis: a step closer to solving joint stiffness. Rheumatology (Oxford) 54, 1954\u20131963 (2015).","journal-title":"Rheumatology (Oxford)"},{"key":"47391_CR8","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1136\/annrheumdis-2018-212964","volume":"77","author":"X Tang","year":"2018","unstructured":"Tang, X. et al. Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGF\u03b2. Ann Rheum Dis 77, 1372\u20131380 (2018).","journal-title":"Ann Rheum Dis"},{"key":"47391_CR9","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1002\/art.40056","volume":"69","author":"E Barboza","year":"2017","unstructured":"Barboza, E. et al. Profibrotic Infrapatellar Fat Pad Remodeling Without M1 Macrophage Polarization Precedes Knee Osteoarthritis in Mice With Diet-Induced Obesity. Arthritis Rheumatol 69, 1221\u20131232 (2017).","journal-title":"Arthritis Rheumatol"},{"key":"47391_CR10","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1177\/1759720X12467868","volume":"5","author":"J Sokolove","year":"2013","unstructured":"Sokolove, J. & Lepus, C. M. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther Adv Musculoskelet Dis 5, 77\u201394 (2013).","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"47391_CR11","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1002\/art.21795","volume":"54","author":"ENB Davidson","year":"2006","unstructured":"Davidson, E. N. B. et al. Connective tissue growth factor\/CCN2 overexpression in mouse synovial lining results in transient fibrosis and cartilage damage. Arthritis Rheum 54, 1653\u20131661 (2006).","journal-title":"Arthritis Rheum"},{"key":"47391_CR12","doi-asserted-by":"publisher","first-page":"847","DOI":"10.5966\/sctm.2015-0245","volume":"5","author":"Y-M Pers","year":"2016","unstructured":"Pers, Y.-M. et al. Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial. Stem Cells Transl Med 5, 847\u2013856 (2016).","journal-title":"Stem Cells Transl Med"},{"key":"47391_CR13","first-page":"11","volume":"9","author":"AI Caplan","year":"2011","unstructured":"Caplan, A. I. & Correa, D. The MSC: an injury drugstore. 9, 11\u201315 (2011).","journal-title":"The MSC: an injury drugstore."},{"key":"47391_CR14","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1146\/annurev-pathol-011110-130230","volume":"6","author":"NG Singer","year":"2011","unstructured":"Singer, N. G. & Caplan, A. I. Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 6, 457\u2013478 (2011).","journal-title":"Annu Rev Pathol"},{"key":"47391_CR15","doi-asserted-by":"publisher","first-page":"e10088","DOI":"10.1371\/journal.pone.0010088","volume":"5","author":"RS Waterman","year":"2010","unstructured":"Waterman, R. S., Tomchuck, S. L., Henkle, S. L. & Betancourt, A. M. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE 5, e10088 (2010).","journal-title":"PLoS ONE"},{"key":"47391_CR16","doi-asserted-by":"crossref","unstructured":"Bernardo, M. E. & Fibbe, W. E. Mesenchymal stromal cells: sensors and switchers of inflammation. 13, 392\u2013402 (2013).","DOI":"10.1016\/j.stem.2013.09.006"},{"key":"47391_CR17","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.jcyt.2015.11.008","volume":"18","author":"J Galipeau","year":"2016","unstructured":"Galipeau, J. et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 18, 151\u2013159 (2016).","journal-title":"Cytotherapy"},{"key":"47391_CR18","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/nyas.12815","volume":"1351","author":"A Uccelli","year":"2015","unstructured":"Uccelli, A. & de Rosbo, N. K. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci 1351, 114\u2013126 (2015).","journal-title":"Ann N Y Acad Sci"},{"key":"47391_CR19","doi-asserted-by":"publisher","first-page":"e0193178","DOI":"10.1371\/journal.pone.0193178","volume":"13","author":"RL Kadle","year":"2018","unstructured":"Kadle, R. L. et al. Microenvironmental cues enhance mesenchymal stem cell-mediated immunomodulation and regulatory T-cell expansion. PLoS ONE 13, e0193178 (2018).","journal-title":"PLoS ONE"},{"key":"47391_CR20","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1038\/leu.2011.108","volume":"25","author":"M Krampera","year":"2011","unstructured":"Krampera, M. Mesenchymal stromal cell \u2018licensing\u2019: a multistep process. Leukemia 25, 1408\u20131414 (2011).","journal-title":"Leukemia"},{"key":"47391_CR21","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.1016\/j.transproceed.2009.06.119","volume":"41","author":"P Renner","year":"2009","unstructured":"Renner, P. et al. Mesenchymal stem cells require a sufficient, ongoing immune response to exert their immunosuppressive function. Transplant Proc 41, 2607\u20132611 (2009).","journal-title":"Transplant Proc"},{"key":"47391_CR22","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1002\/jor.20498","volume":"26","author":"B Lehner","year":"2008","unstructured":"Lehner, B. et al. Preponderance of sensory versus sympathetic nerve fibers and increased cellularity in the infrapatellar fat pad in anterior knee pain patients after primary arthroplasty. J Orthop Res 26, 342\u2013350 (2008).","journal-title":"J Orthop Res"},{"key":"47391_CR23","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1007\/s00402-005-0796-4","volume":"125","author":"M Bohnsack","year":"2005","unstructured":"Bohnsack, M. et al. Distribution of substance-P nerves inside the infrapatellar fat pad and the adjacent synovial tissue: a neurohistological approach to anterior knee pain syndrome. Arch Orthop Trauma Surg 125, 592\u2013597 (2005).","journal-title":"Arch Orthop Trauma Surg"},{"key":"47391_CR24","doi-asserted-by":"publisher","DOI":"10.1186\/s13018-016-0359-0","volume":"11","author":"FX Koeck","year":"2016","unstructured":"Koeck, F. X. et al. Predominance of synovial sensory nerve fibers in arthrofibrosis following total knee arthroplasty compared to osteoarthritis of the knee. Journal of orthopaedic surgery and research 11, 25 (2016).","journal-title":"Journal of orthopaedic surgery and research"},{"key":"47391_CR25","doi-asserted-by":"publisher","first-page":"4249","DOI":"10.1007\/s00018-016-2293-z","volume":"73","author":"A Mashaghi","year":"2016","unstructured":"Mashaghi, A. et al. Neuropeptide substance P and the immune response. Cell Mol Life Sci 73, 4249\u20134264 (2016).","journal-title":"Cell Mol Life Sci"},{"key":"47391_CR26","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1189\/jlb.1AB0416-188RR","volume":"101","author":"S Spitsin","year":"2017","unstructured":"Spitsin, S. et al. Substance P\u2013mediated chemokine production promotes monocyte migration. Journal of Leukocyte Biology 101, 967\u2013973 (2017).","journal-title":"Journal of Leukocyte Biology"},{"key":"47391_CR27","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.bbrc.2017.02.036","volume":"485","author":"S Kim","year":"2017","unstructured":"Kim, S. Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro. Biochem Biophys Res Commun 485, 131\u2013137 (2017).","journal-title":"Biochem Biophys Res Commun"},{"key":"47391_CR28","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cyto.2014.10.003","volume":"71","author":"Y Jin","year":"2015","unstructured":"Jin, Y., Hong, H. S. & Son, Y. Substance P enhances mesenchymal stem cells-mediated immune modulation. Cytokine 71, 145\u2013153 (2015).","journal-title":"Cytokine"},{"key":"47391_CR29","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.stemcr.2014.01.002","volume":"2","author":"WK Ong","year":"2014","unstructured":"Ong, W. K. et al. Identification of specific cell-surface markers of adipose-derived stem cells from subcutaneous and visceral fat depots. Stem Cell Reports 2, 171\u2013179 (2014).","journal-title":"Stem Cell Reports"},{"key":"47391_CR30","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1002\/stem.1681","volume":"32","author":"F-J Lv","year":"2014","unstructured":"Lv, F.-J., Tuan, R. S., Cheung, K. M. C. & Leung, V. Y. L. Concise review: the surface markers and identity of human mesenchymal stem cells. STEM CELLS 32, 1408\u20131419 (2014).","journal-title":"STEM CELLS"},{"key":"47391_CR31","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1002\/stem.592","volume":"29","author":"V Maguer-Satta","year":"2011","unstructured":"Maguer-Satta, V., Besan\u00e7on, R. & Bachelard-Cascales, E. Concise review: neutral endopeptidase (CD10): a multifaceted environment actor in stem cells, physiological mechanisms, and cancer. STEM CELLS 29, 389\u2013396 (2011).","journal-title":"STEM CELLS"},{"key":"47391_CR32","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s00403-010-1093-9","volume":"303","author":"L Xie","year":"2011","unstructured":"Xie, L. et al. CD10-bearing fibroblasts may inhibit skin inflammation by down-modulating substance P. Arch. Dermatol. Res. 303, 49\u201355 (2011).","journal-title":"Arch. Dermatol. Res."},{"key":"47391_CR33","doi-asserted-by":"publisher","first-page":"4019873","DOI":"10.1155\/2016\/4019873","volume":"2016","author":"P Tangchitphisut","year":"2016","unstructured":"Tangchitphisut, P. et al. Infrapatellar Fat Pad: An Alternative Source of Adipose-Derived Mesenchymal Stem Cells. Arthritis 2016, 4019873\u201310 (2016).","journal-title":"Arthritis"},{"key":"47391_CR34","first-page":"49","volume":"96","author":"W Zieglg\u00e4nsberger","year":"2018","unstructured":"Zieglg\u00e4nsberger, W. & Substance, P. and pain chronicity. Cell Tissue Res 96, 49 (2018).","journal-title":"Cell Tissue Res"},{"key":"47391_CR35","doi-asserted-by":"publisher","first-page":"1484","DOI":"10.1016\/j.joca.2012.08.027","volume":"20","author":"BJE de Lange-Brokaar","year":"2012","unstructured":"de Lange-Brokaar, B. J. E. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthr Cartil 20, 1484\u20131499 (2012).","journal-title":"Osteoarthr Cartil"},{"key":"47391_CR36","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1016\/j.joca.2015.02.009","volume":"23","author":"HN Daghestani","year":"2015","unstructured":"Daghestani, H. N. & Kraus, V. B. Inflammatory biomarkers in osteoarthritis. Osteoarthr Cartil 23, 1890\u20131896 (2015).","journal-title":"Osteoarthr Cartil"},{"key":"47391_CR37","doi-asserted-by":"publisher","first-page":"491","DOI":"10.3389\/fimmu.2014.00491","volume":"5","author":"G Arango Duque","year":"2014","unstructured":"Arango Duque, G. & Descoteaux, A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 5, 491 (2014).","journal-title":"Front Immunol"},{"key":"47391_CR38","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.biochi.2010.11.010","volume":"93","author":"L Kular","year":"2011","unstructured":"Kular, L., Pakradouni, J., Kitabgi, P., Laurent, M. & Martinerie, C. The CCN family: A new class of inflammation modulators? Biochimie 93, 377\u2013388 (2011).","journal-title":"Biochimie"},{"key":"47391_CR39","doi-asserted-by":"publisher","first-page":"877","DOI":"10.3892\/mmr.2013.1570","volume":"8","author":"Z Wang","year":"2013","unstructured":"Wang, Z., Qiu, Y., Lu, J. & Wu, N. A. Connective tissue growth factor promotes interleukin-1\u03b2-mediated synovial inflammation in knee osteoarthritis. Mol Med Rep 8, 877\u2013882 (2013).","journal-title":"Mol Med Rep"},{"key":"47391_CR40","doi-asserted-by":"publisher","first-page":"e51097","DOI":"10.1371\/journal.pone.0051097","volume":"7","author":"S-C Liu","year":"2012","unstructured":"Liu, S.-C. et al. CTGF Increases IL-6 Expression in Human Synovial Fibroblasts through Integrin-Dependent Signaling Pathway. PLoS ONE 7, e51097 (2012).","journal-title":"PLoS ONE"},{"key":"47391_CR41","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1016\/j.bbamcr.2012.12.014","volume":"1833","author":"S-C Liu","year":"2013","unstructured":"Liu, S.-C., Hsu, C.-J., Fong, Y.-C., Chuang, S.-M. & Tang, C.-H. CTGF induces monocyte chemoattractant protein-1 expression to enhance monocyte migration in human synovial fibroblasts. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1833, 1114\u20131124 (2013).","journal-title":"Biochimica et Biophysica Acta (BBA) - Molecular Cell Research"},{"key":"47391_CR42","doi-asserted-by":"publisher","first-page":"303","DOI":"10.3109\/1354750X.2012.666676","volume":"17","author":"S Honsawek","year":"2012","unstructured":"Honsawek, S. et al. Plasma and synovial fluid connective tissue growth factor levels are correlated with disease severity in patients with knee osteoarthritis. Biomarkers 17, 303\u2013308 (2012).","journal-title":"Biomarkers"},{"key":"47391_CR43","doi-asserted-by":"publisher","first-page":"3340","DOI":"10.1172\/JCI43230","volume":"120","author":"CH Lee","year":"2010","unstructured":"Lee, C. H., Shah, B., Moioli, E. K. & Mao, J. J. CTGF directs fibroblast differentiation from human mesenchymal stem\/stromal cells and defines connective tissue healing in a rodent injury model. J Clin Invest 120, 3340\u20133349 (2010).","journal-title":"J Clin Invest"},{"key":"47391_CR44","doi-asserted-by":"publisher","first-page":"6162","DOI":"10.1016\/j.biomaterials.2012.05.037","volume":"33","author":"Y-Q Guan","year":"2012","unstructured":"Guan, Y.-Q. et al. Cell cycle arrest and apoptosis of OVCAR-3 and MCF-7 cells induced by co-immobilized TNF-\u03b1 plus IFN-\u03b3 on polystyrene and the role of p53 activation. Biomaterials 33, 6162\u20136171 (2012).","journal-title":"Biomaterials"},{"key":"47391_CR45","doi-asserted-by":"publisher","first-page":"298","DOI":"10.22203\/eCM.v027a21","volume":"27","author":"S Lopa","year":"2014","unstructured":"Lopa, S. et al. Donor-matched mesenchymal stem cells from knee infrapatellar and subcutaneous adipose tissue of osteoarthritic donors display differential chondrogenic and osteogenic commitment. Eur Cell Mater 27, 298\u2013311 (2014).","journal-title":"Eur Cell Mater"},{"key":"47391_CR46","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.1089\/ten.tea.2014.0035","volume":"20","author":"Y Liu","year":"2014","unstructured":"Liu, Y., Buckley, C. T., Almeida, H. V., Mulhall, K. J. & Kelly, D. J. Infrapatellar fat pad-derived stem cells maintain their chondrogenic capacity in disease and can be used to engineer cartilaginous grafts of clinically relevant dimensions. Tissue Eng Part A 20, 3050\u20133062 (2014).","journal-title":"Tissue Eng Part A"},{"key":"47391_CR47","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.jcyt.2013.02.006","volume":"15","author":"P Bourin","year":"2013","unstructured":"Bourin, P. et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal\/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641\u2013648 (2013).","journal-title":"Cytotherapy"},{"key":"47391_CR48","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1080\/14653240600855905","volume":"8","author":"M Dominici","year":"2006","unstructured":"Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315\u2013317 (2006).","journal-title":"Cytotherapy"},{"key":"47391_CR49","doi-asserted-by":"publisher","first-page":"77","DOI":"10.5966\/sctm.2016-0040","volume":"6","author":"P Hindle","year":"2017","unstructured":"Hindle, P., Khan, N., Biant, L. & P\u00e9ault, B. The Infrapatellar Fat Pad as a Source of Perivascular Stem Cells with Increased Chondrogenic Potential for Regenerative Medicine. Stem Cells Transl Med 6, 77\u201387 (2017).","journal-title":"Stem Cells Transl Med"},{"key":"47391_CR50","doi-asserted-by":"publisher","first-page":"5067","DOI":"10.1182\/blood-2010-08-304287","volume":"117","author":"A Tormin","year":"2011","unstructured":"Tormin, A. et al. CD146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood 117, 5067\u20135077 (2011).","journal-title":"Blood"},{"key":"47391_CR51","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1002\/art.27595","volume":"62","author":"E Jones","year":"2010","unstructured":"Jones, E. et al. Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum 62, 1944\u20131954 (2010).","journal-title":"Arthritis Rheum"},{"key":"47391_CR52","doi-asserted-by":"publisher","first-page":"561098","DOI":"10.1155\/2013\/561098","volume":"2013","author":"LA Marquez-Curtis","year":"2013","unstructured":"Marquez-Curtis, L. A. & Janowska-Wieczorek, A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1\/CXCR4 axis. BioMed Research International 2013, 561098\u201315 (2013).","journal-title":"BioMed Research International"},{"key":"47391_CR53","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1111\/jcmm.12752","volume":"20","author":"C Pontikoglou","year":"2016","unstructured":"Pontikoglou, C. et al. CD200 expression in human cultured bone marrow mesenchymal stem cells is induced by pro-osteogenic and pro-inflammatory cues. J Cell Mol Med 20, 655\u2013665 (2016).","journal-title":"J Cell Mol Med"},{"key":"47391_CR54","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.cell.2007.08.025","volume":"131","author":"B Sacchetti","year":"2007","unstructured":"Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324\u2013336 (2007).","journal-title":"Cell"},{"key":"47391_CR55","doi-asserted-by":"publisher","first-page":"0118","DOI":"10.1089\/ten.TEB.2018.0118","volume":"2018","author":"D Kouroupis","year":"2018","unstructured":"Kouroupis, D., Sanjurjo-Rodriguez, C., Jones, E. & Correa, D. MSC functionalization for enhanced therapeutic applications. Tissue Eng Part B Rev ten.TEB. 2018, 0118, https:\/\/doi.org\/10.1089\/ten.TEB.2018.0118 (2018).","journal-title":"Tissue Eng Part B Rev ten.TEB."},{"key":"47391_CR56","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.immuni.2015.01.020","volume":"42","author":"DMW Zaiss","year":"2015","unstructured":"Zaiss, D. M. W., Gause, W. C., Osborne, L. C. & Artis, D. Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair. Immunity 42, 216\u2013226 (2015).","journal-title":"Immunity"},{"key":"47391_CR57","doi-asserted-by":"publisher","first-page":"2321","DOI":"10.4049\/jimmunol.0902023","volume":"184","author":"G Ren","year":"2010","unstructured":"Ren, G. et al. Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression. J Immunol 184, 2321\u20132328 (2010).","journal-title":"J Immunol"},{"key":"47391_CR58","first-page":"2504","volume":"22","author":"R Chinnadurai","year":"2018","unstructured":"Chinnadurai, R. et al. Potency Analysis of Mesenchymal Stromal Cells Using a Combinatorial Assay Matrix Approach. CellReports 22, 2504\u20132517 (2018).","journal-title":"CellReports"},{"key":"47391_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/srep14382","volume":"5","author":"A Madej-Michniewicz","year":"2015","unstructured":"Madej-Michniewicz, A. et al. Evaluation of selected interleukins in patients with different gastric neoplasms: a preliminary report. Sci Rep 5, 14382 (2015).","journal-title":"Sci Rep"},{"key":"47391_CR60","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cyto.2016.12.001","volume":"91","author":"BA Barajas-G\u00f3mez","year":"2017","unstructured":"Barajas-G\u00f3mez, B. A. et al. Relationship of inflammatory profile of elderly patients serum and senescence-associated secretory phenotype with human breast cancer cells proliferation: Role of IL6\/IL8 ratio. Cytokine 91, 13\u201329 (2017).","journal-title":"Cytokine"},{"key":"47391_CR61","first-page":"399","volume":"49","author":"JP Sikora","year":"2001","unstructured":"Sikora, J. P., Chlebna-Sok\u00f3\u0142, D. & Krzyza\u0144ska-Oberbek, A. Proinflammatory cytokines (IL-6, IL-8), cytokine inhibitors (IL-6sR, sTNFRII) and anti-inflammatory cytokines (IL-10, IL-13) in the pathogenesis of sepsis in newborns and infants. Arch Immunol Ther Exp (Warsz) 49, 399\u2013404 (2001).","journal-title":"Arch Immunol Ther Exp (Warsz)"},{"key":"47391_CR62","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1093\/jmcb\/mjt030","volume":"5","author":"S Rayego-Mateos","year":"2013","unstructured":"Rayego-Mateos, S. et al. Connective tissue growth factor is a new ligand of epidermal growth factor receptor. J Mol Cell Biol 5, 323\u2013335 (2013).","journal-title":"J Mol Cell Biol"},{"key":"47391_CR63","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1681\/ASN.2003100905","volume":"16","author":"NA Wahab","year":"2005","unstructured":"Wahab, N. A., Weston, B. S. & Mason, R. M. Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA. JASN 16, 340\u2013351 (2005).","journal-title":"JASN"},{"key":"47391_CR64","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1002\/stem.2575","volume":"35","author":"DG Phinney","year":"2017","unstructured":"Phinney, D. G. & Pittenger, M. F. Concise Review: MSC\u2010Derived Exosomes for Cell\u2010Free Therapy. STEM CELLS 35, 851\u2013858 (2017).","journal-title":"STEM CELLS"},{"key":"47391_CR65","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1002\/stem.2730","volume":"36","author":"MT Harting","year":"2017","unstructured":"Harting, M. T. et al. Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation. STEM CELLS 36, 79\u201390 (2017).","journal-title":"STEM CELLS"},{"key":"47391_CR66","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1007\/s12026-016-8798-6","volume":"64","author":"W Chen","year":"2016","unstructured":"Chen, W. et al. Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunologic Research 64, 831\u2013840 (2016).","journal-title":"Immunologic Research"},{"key":"47391_CR67","doi-asserted-by":"publisher","DOI":"10.1038\/srep01197","volume":"3","author":"T Katsuda","year":"2013","unstructured":"Katsuda, T. et al. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 3, 1197 (2013).","journal-title":"Sci Rep"},{"key":"47391_CR68","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.4049\/jimmunol.1601751","volume":"199","author":"S Suvas","year":"2017","unstructured":"Suvas, S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue Homeostasis. J Immunol 199, 1543\u20131552 (2017).","journal-title":"J Immunol"},{"key":"47391_CR69","doi-asserted-by":"publisher","first-page":"e0139206","DOI":"10.1371\/journal.pone.0139206","volume":"10","author":"B Lisowska","year":"2015","unstructured":"Lisowska, B., Lisowski, A. & Siewruk, K. Substance P and Chronic Pain in Patients with Chronic Inflammation of Connective Tissue. PLoS ONE 10, e0139206 (2015).","journal-title":"PLoS ONE"},{"key":"47391_CR70","doi-asserted-by":"publisher","first-page":"1284","DOI":"10.1016\/j.joca.2016.02.005","volume":"24","author":"M Udo","year":"2016","unstructured":"Udo, M. et al. Monoiodoacetic acid induces arthritis and synovitis in rats in a dose- and time-dependent manner: proposed model-specific scoring systems. Osteoarthr Cartil 24, 1284\u20131291 (2016).","journal-title":"Osteoarthr Cartil"},{"key":"47391_CR71","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nbt.2816","volume":"32","author":"JA Ankrum","year":"2014","unstructured":"Ankrum, J. A., Ong, J. F. & Karp, J. M. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 32, 252\u2013260 (2014).","journal-title":"Nat Biotechnol"},{"key":"47391_CR72","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1038\/mt.2013.221","volume":"22","author":"P Lin","year":"2014","unstructured":"Lin, P. et al. Serial transplantation and long-term engraftment of intra-arterially delivered clonally derived mesenchymal stem cells to injured bone marrow. Mol Ther 22, 160\u2013168 (2014).","journal-title":"Mol Ther"},{"key":"47391_CR73","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13287-015-0253-4","volume":"7","author":"M Li","year":"2016","unstructured":"Li, M. et al. In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model. Stem Cell Res Ther 7, 1\u201313 (2016).","journal-title":"Stem Cell Res Ther"},{"key":"47391_CR74","doi-asserted-by":"publisher","first-page":"124","DOI":"10.3109\/08916934.2015.1113267","volume":"49","author":"U Skalska","year":"2015","unstructured":"Skalska, U. & Kontny, E. Adipose-derived mesenchymal stem cells from infrapatellar fat pad of patients with rheumatoid arthritis and osteoarthritis have comparable immunomodulatory properties. Autoimmunity 49, 124\u2013131 (2015).","journal-title":"Autoimmunity"},{"key":"47391_CR75","first-page":"571","volume":"13","author":"L Lieben","year":"2017","unstructured":"Lieben, L. Rheumatoid arthritis: Characterization of the infrapatellar fat pad. Nature Reviews. Rheumatology 13, 571\u2013571 (2017).","journal-title":"Rheumatology"},{"key":"47391_CR76","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1136\/annrheumdis-2017-211673","volume":"77","author":"AJ de Jong","year":"2018","unstructured":"de Jong, A. J. et al. Inflammatory features of infrapatellar fat pad in rheumatoid arthritis versus osteoarthritis reveal mostly qualitative differences. Ann Rheum Dis 77, 1088\u20131090 (2018).","journal-title":"Ann Rheum Dis"},{"key":"47391_CR77","doi-asserted-by":"publisher","first-page":"D447","DOI":"10.1093\/nar\/gku1003","volume":"43","author":"D Szklarczyk","year":"2015","unstructured":"Szklarczyk, D. et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447\u201352 (2015).","journal-title":"Nucleic Acids Res."},{"key":"47391_CR78","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.joca.2012.02.010","volume":"20","author":"C Kilkenny","year":"2012","unstructured":"Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. Osteoarthritis and cartilage \/ OARS, Osteoarthritis Research Society 20, 256\u2013260 (2012).","journal-title":"Osteoarthritis and cartilage \/ OARS, Osteoarthritis Research Society"},{"key":"47391_CR79","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1469-7580.2007.00791.x","volume":"211","author":"HM Shaw","year":"2007","unstructured":"Shaw, H. M., Santer, R. M., Watson, A. H. D. & Benjamin, M. Adipose tissue at entheses: the innervation and cell composition of the retromalleolar fat pad associated with the rat Achilles tendon. J Anat 211, 436\u2013??? (2007).","journal-title":"J Anat"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47391-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47391-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47391-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,21]],"date-time":"2024-07-21T07:17:59Z","timestamp":1721546279000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-47391-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,26]]},"references-count":79,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["47391"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-47391-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,26]]},"assertion":[{"value":"17 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Diego Correa is a paid consultant of Lipogems International SpA.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"10864"}}